Exomic Sequencing of Four Rare Central Nervous System Tumor Types

// Chetan Bettegowda 1,2,* , Nishant Agrawal 2,3,* , Yuchen Jiao 2,* , Yuxuan Wang 2 , Laura D. Wood 4 , Fausto J. Rodriguez 4 , Ralph H. Hruban 4 , Gary L. Gallia 1 , Zev A. Binder 1 , Callen J. Riggins 1 , Vafi Salmasi 5 , Gregory J. Riggins 1 , Zachary J. Reitman 6 , Ahmed Rasheed 6 , Stephen Keir 6 , Sueli Shinjo 7 , Suely Marie 7 , Roger McLendon 6 , George Jallo 1 , Bert Vogelstein 2 , Darell Bigner 6 , Hai Yan 6 , Kenneth W. Kinzler 2 and Nickolas Papadopoulos 2 1 Department of Neurosurgery, Johns Hopkins University School of Medicine, Baltimore, MD, USA 2 Ludwig Center for Cancer Genetics, Johns Hopkins University School of Medicine, Baltimore, MD, USA 3 Department of Otolaryngology-Head and Neck Surgery, Johns Hopkins University School of Medicine, Baltimore, MD, USA 4 Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD USA 5 Department of Anesthesiology, Cleveland Clinic Hospital, Cleveland, OH USA 6 Preston Robert Tisch Brain Tumor Center, Duke University Medical Center, Durham, NC, USA 7 Department of Pathology, University of São Paulo School of Medicine, São Paulo, Brazil * C.B., N.A. and Y.J. contributed equally as first authors. Correspondence: Chetan Bettegowda , email: // Kenneth W. Kinzler , email: // Nickolas Papadopoulos , email: // Keywords : Central nervous system (CNS) tumors, cancer genetics, exome sequencing, pediatric tumors, brain tumors. Received : April 4, 2013 Accepted : April 6, 2013 Published : April 6, 2013 Abstract A heterogeneous population of uncommon neoplasms of the central nervous system (CNS) cause significant morbidity and mortality. To explore their genetic origins, we sequenced the exomes of 12 pleomorphic xanthoastrocytomas (PXA), 17 non-brainstem pediatric glioblastomas (PGBM), 8 intracranial ependymomas (IEP) and 8 spinal cord ependymomas (SCEP). Analysis of the mutational spectra revealed that the predominant single base pair substitution was a C:G>T:A transition in each of the four tumor types. Our data confirm the critical roles of several known driver genes within CNS neoplasms, including TP53 and ATRX in PGBM, and NF2 in SCEPs. Additionally, we show that activating BRAF mutations play a central role in both low and high grade glial tumors. Furthermore, alterations in genes coding for members of the mammalian target of rapamycin (mTOR) pathway were observed in 33% of PXA. Our study supports the hypothesis that pathologically similar tumors arising in different age groups and from different compartments may represent distinct disease processes with varied genetic composition.